Tuesday, October 30, 2007

In the previous post, The Neurocritic discussed an article in Nature in which greater activity in the rostral anterior cingulate cortex (rACC) was associated with optimism1 (Sharot et al., 2007). "But wait!" you might say, "what about the sad cingulate?" Neuroimaging studies have shown that the sad subgenual cingulate (Brodmann area 25), located beneath the genu of the corpus callosum, is overly active in depression (Mayberg et al., 2000; see also Greicius et al., 2007). This excessive activity is dampened in those who respond to six weeks of fluoxetine treatment (Prozac, an SSRI antidepressant), but remains elevated in those who don't. Is this the same brain region in the two experiments? Let's take a look.

On the left is Fig. 2a of Mayberg et al. (2000), showing a decrease in area 25 (Cg25) activity in fluoxetine responders, as measured by PET. On the right is Fig. 2b of Sharot et al. (2007), showing the optimistic rACC region. At first glance, the two "hot spots" appear to be in quite similar locations. However, there are differences in the precise centers of mass, as indicated by the respective x y z coordinates (according to Talairach and Tournoux, a standard 3D atlas of the human brain), and in the designated Brodmann areas (numbered cortical regions based on cytoarchitecture).

x, y, z

BA

Mayberg

10,22,-14

25

Sharot

-11, 42, -1

32

The x coordinate indicates right or left hemisphere, y is anterior/posterior, and z is dorsal/ventral. Although activations in medial structures generally aren't discussed in terms of left/right hemisphere, because the margin of error is often greater than the distance from the midline (x = 0), here they're centered 10 mm right and 11 mm left of midline, respectively. Furthermore, the Sharot activation is 20 mm in front of the Mayberg activation. Finally, the activations are indicated by different Brodmann areas. Hmm, not the same.

More recently, Mayberg's group demonstrated that deep brain stimulation (DBS) in area 25 was effective in treating severe intractable depression in a small group of patients (Mayberg et al., 2005).

Each [of the six patients] met stringent criteria for treatment resistance defined as failure to response to a minimum of four different antidepressant treatments, including medications, evidence-based psychotherapy, or electroconvulsive therapy, administered at adequate doses and duration during the current episode.

In this procedure, a stimulating electrode is stereotaxically implanted in the targeted region. Dr. Helen Mayberg and her colleagues at Emory University are still recruiting patients with treatment resistant depression to participate in a clinical trial using chronic, high frequency stimulation of the subgenual cingulate white matter. To determine the anatomical connectivity of the sad cingulate region, a new study performed tractography (using diffusion-weighted magnetic resonance imaging) to trace the pathways mediating treatment response with DBS (Johansen-Berg et al., 2007). The authors compared the connections of the subgenual ACC (sACC, blue/cyan) and the perigenual ACC (pACC, red/yellow), which appears to be the optimistic rACC region of Sharot and colleagues.

Can we directly link the "optimistic rACC" (pACC) to depression, as stated in the Nature paper? Or more specifically, to DBS efficacy [and Prozac efficacy], as indicated by the work of Mayberg and colleagues? Not really. The effective electrode contacts were in sACC. The critical comparison of sACC vs. pACC connectivity is illustrated below. Is the latter highly interconnected with the amygdala? Doesn't seem to be.

How do we account for these discrepancies in the Nature paper? The tractography article was published after the former went to press, but earlier work by Mayberg et al. was neglected. However, other results were cited (Drevets et al., 1997). These investigators found resting metabolic activity in ventral ACC to be reduced in both unipolar and bipolar depression, contrary to sad cingulate hyperactivity. What's up with that? Here's what Mayberg et al. (2005) suggest:

The baseline pattern of subgenual cingulate hyperactivity in combination with frontal hypoactivity described here in this TRD patient group is a finding that is in contrast to the hypoactivity reported in a more rostral region of subgenual medial prefrontal cortex in familial bipolar and unipolar depressed patients (Drevets et al., 1997). This distinction suggests important differences across subtypes of depression that are potentially relevant to the pathophysiology of major depressive disorders and perhaps their treatment.

What have we learned? Location matters. It's helpful to read the literature. So it goes...

Chronic deep brain stimulation (DBS) of subgenual cingulate white matter results in dramatic remission of symptoms in some previously treatment-resistant depression patients. The effects of stimulation may be mediated locally or via corticocortical or corticosubcortical connections. We use tractography to define the likely connectivity of cingulate regions stimulated in DBS-responsive patients using diffusion imaging data acquired in healthy control subjects. We defined 2 distinct regions within anterior cingulate cortex based on anatomical connectivity: a pregenual region strongly connected to medial prefrontal and anterior midcingulate cortex and a subgenual region with strongest connections to nucleus accumbens, amygdala, hypothalamus, and orbitofrontal cortex. The location of electrode contact points from 9 patients successfully treated with DBS lies within this subgenual region. The anatomical connectivity of the subgenual cingulate region targeted with DBS for depression supports the hypothesis that treatment efficacy is mediated via effects on a distributed network of frontal, limbic, and visceromotor brain regions. At present, targeting of DBS for depression is based on landmarks visible in conventional magnetic resonance imaging. Preoperatively acquired diffusion imaging for connectivity-based cortical mapping could improve neurosurgical targeting. We hypothesize that the subgenual region with greatest connectivity across the distributed network described here may prove most effective.

10 Comments:

Are you sure that the difference isn't due to any MNI/Talairach coordinate system differences? The former is confusingly referred to as Talairach frequently. As you probably know, the two systems are nearly identical for subcortical systems but get increasing misaligned in cortical regions.

Neurocritic: “The Neurocritic discussed an article in Nature in which greater activity in the rostral anterior cingulate cortex (rACC) was associated with optimism1 (Sharot et al., 2007). "But wait!" you might say, "what about the sad cingulate?" Neuroimaging studies have shown that the sad subgenual cingulate (Brodmann area 25), located beneath the genu of the corpus callosum, is overly active in depression (Mayberg et al., 2000; see also Greicius et al., 2007).”But wait… did the neurocritic actually read the Nature paper carefully? If he had he might have seen this:“….it has been shown that the rACC’s response to positive and negative stimuli reflects situational specificity. For example, both the rACC and amygdala were more sensitive to positive stimuli in subjects that focused on obtaining goals (promotional context) and to negative stimuli in subjects that focused on avoiding failure (prevention context)22..... in the current study the rACC is tracking the subjective salience of the stimuli by assessing emotional, motivational and autobiographical information, and possibly regulating such signals…”In other words, the rACC may show greater activity in response to positive events in optimistic subjects, but greater activity to negative events in pessimistic (depressed?) subjects. Indeed, this is what was reported in this paper.

One major point of this post was to explore, and question, whether the rACC region reported by Sharot et al. (2007) is the same one that has been implicated in major depression by Mayberg et al. These two may not be the same region (in my humble estimation). Another point was to examine Sharot et al.'s results in light of the new DTI findings from Johansen-Berg et al. (2007), in terms of connectivity to the amygdala (which is substantial for subgenual area 25, not so much for rACC).

These two issues are independent of the comments from the New Anonymous...

It seems there is a basic misunderstanding regarding the spatial resolution of fMRI. Unfortunately one cannot make specific spatial localization with conventional fMRI. All the fMRI studies cited here used convention (low-resolution) fMRI + spatial smoothing in data analysis + averaging across brains. The fMRI peaks reported indicate approximate localization. They are reported to give the reader a general idea of localization. Furthermore, they are only the localization of the peak affect. The affect usually spreads beyond the peak. For this reason in most studies discussion of localization in the conclusion is worded in general terms (i.e – rACC and not BA 32). Thus, the comparisons above are not very meaningfull.

There are gross anatomical variations from one brain to another. I often find it striking that Talairach coordinates are still used because they're based on some 80-year old french alcoholic woman's brain. The MNI series is a better estimation of anatomical localization when it comes to aggregating regions and making claims about activation and source localization. Overall, fMRI has a lot of problems, but it still remains a sophisticated and useful methodology. One must be aware of its cavaets when reading about fMRI findings and what can be surmised from them.

Overall, the rostral cingulate seems to be important for salience detection. It being highly innervated with the amgydala suggests that the rACC is important for purposive, goal-directed behavior in the presence of salient environmental cues. It's all rather fascinating, but makes it easy to endorse a neo-phrenological view of the brain, which is folly. The brain is a dynamic system, and fMRI only shows signal-to-noise ratios of areas, but the entire brain is always active and interacting with many other areas. Its astonishing complexity is often simplifed to make it more palatable, but often at the cost of ontological validty, if I may be so bold.

My psychiatrist and I are discussing the possibility of my undergoing a bilateral anterior cingulotomy. I was wondering why cingulotomies choose the lesion location they do, and what effect does this have on the 'sad cingulate' and the 'happy cingulate', as well as, possibly, if anyone knows, effects on other limbic areas e.g. amygdala due to its afferent and efferent connections thereto. Sorry for my simplistic questions, I am but a decade long severely depressed layman.

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Born in West Virginia in 1980, The Neurocritic embarked upon a roadtrip across America at the age of thirteen with his mother. She abandoned him when they reached San Francisco and The Neurocritic descended into a spiral of drug abuse and prostitution. At fifteen, The Neurocritic's psychiatrist encouraged him to start writing as a form of therapy.